Distinct clinical phenotype and genetic testing strategy for Lynch syndrome in China based on a large colorectal cancer cohort

Abstract

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) predisposition syndrome. We performed a large‐scale study to assess a screening strategy for identifying LS in Chinese CRC patients in routine clinical testing. A total of 4,195 eligible CRCs were universally screened. Then, 8.7% of CRCs were detected with dMMR. The incidence of LS was 2.7% (115 of 4,195) in this cohort; among patients over 70 years of age, only 0.3% (2 of 678) were diagnosed as LS. Then, 17.4% of LS cases showed large genomic deletions/duplications. LS probands developed CRCs predominantly at proximal colon location. The frequency of BRAF V600E mutation among Chinese CRCs was significantly lower than that among Western populations, and MLH1 promoter methylation significantly improved the efficiency of genetic screening for LS among MLH1‐deficient patients. A comprehensive molecular testing strategy that includes detection of large genomic rearrangements is imperative for the diagnosis of LS. Among CRC patients aged 70 years or younger, a selective strategy for LS screening might be considered for routine clinical testing.

Cytoplasmic MSH2 Related to Genomic Deletions in the MSH2/EPCAM Genes in Colorectal Cancer Patients With Suspected Lynch Syndrome

“…Among 4195 eligible patients from the Colorectal Cancer Initiative Screening Program for Lynch Syndrome (CRISPLS) in the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2015 and December 2017, we identified a cohort of 69 patients with loss of the MSH2 and/or MSH6 proteins who had been screened by IHC staining for tumor MMR proteins. Detailed information on the CRISPLS cohort was previously reported (22). Clinicopathological characteristics and information about cancer personal/family history were collected for patients from the CRISPLS cohort who had undergone surgical resection and for whom a sufficient DNA sample was available.…”

“…Formalin-fixed, paraffin-embedded tumors and adjacent normal tissue were collected from the cohort. Genomic DNA was extracted using a TGuide Genomic DNA One-Step Kit and a TGuide Automated Nucleic Acid Preparation Instrument (TIANGEN BIOTECH, Beijing, China) according to the manufacturer's instructions as previously described (22).…”

“…Molecular barcoded DNA libraries were hybridized with a commercial ClearSeq Inherited Disease multigene panel that covered total exons and intron boundaries within at least ±20 bases of the EPCAM, MLH1, PMS2, MSH2 and MSH6 genes (Agilent Technologies). A detailed protocol for variant annotation and classification was described previously (22,25). Diagnosis of LS is dependent on identifying the pathogenic germline variants of MMR genes.…”

“…To estimate the frequency and specificity of MSH2 germline mutations among patients with CRC in the real world, we systematically analyzed a consecutive CRC patient cohort that had been universally screened for LS in our previous study (22). Germline analyses were performed on samples from 69 patients with MSH2-deficient CRC.…”

Germline mutational profile of Chinese patients under 70 years old with colorectal cancer

“…Moreover, limited data, focusing on only MMR genes, have been published about germline hereditary susceptibility in Chinese CRC patients [23]. In our present research, we collected tumor samples from CRC patients diagnosed at the Sun Yat-sen University Cancer Center (SYSUCC; Guangzhou, Guangdong, China), who were recommended to undergo a hereditary CRC 14-gene screening.…”